title: Hypoxanthine guanine phosphoribosyltransferase activity is related to 6-thioguanine nucleotide concentrations and thiopurine-induced leukopenia in the treatment of inflammatory bowel disease.
abstract: BACKGROUND
  Thiopurine drugs are widely used in the treatment of inflammatory bowel disease (IBD). The polymorphic enzyme thiopurine S-methyltransferase (TPMT) is of importance for thiopurine metabolism and adverse events occurrence. The role of other thiopurine-metabolizing enzymes is less well known. This study investigated the effects of TPMT and hypoxanthine guanine phosphoribosyltransferase (HPRT) activities on 6-thioguanine nucleotides (6-TGNs) concentrations and thiopurine-induced leukopenia in patients with IBD.
  
  
  METHODS
  Clinical data and blood samples were collected from 120 IBD patients who were receiving azathioprine (AZA)/6-mercaptopurine (6-MP) therapy. Erythrocyte TPMT, HPRT activities and 6-TGNs concentrations were determined. HPRT activity and its correlation with TPMT activity, 6-TGNs level, and leukopenia were evaluated.
  
  
  RESULTS
  The HPRT activity of all patients ranged from 1.63-3.33 (2.31 ± 0.36) μmol/min per g Hb. HPRT activity was significantly higher in patients with leukopenia (27, 22.5%) than without (P < 0.001). A positive correlation between HPRT activity and 6-TGNs concentration was found in patients with leukopenia (r = 0.526, P = 0.005). Patients with HPRT activity > 2.70 μmol/min per g Hb could have an increased risk of developing leukopenia (odds ratio = 7.47, P < 0.001). No correlation was observed between TPMT activity and HPRT activity, 6-TGNs concentration, or leukopenia.
  
  
  CONCLUSIONS
  High levels of HPRT activity could be a predictor of leukopenia and unsafe 6-TGN concentrations in patients undergoing AZA/6-MP therapy. This could partly explain the therapeutic response or toxicity that could not be adequately explained by the polymorphisms of TPMT.
authors.affiliation: Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, PR China.
authors.forename: Liang
authors.initials: L
authors.lastname: Ding
authors.forename: Fang-bin
authors.initials: FB
authors.lastname: Zhang
authors.forename: Hui
authors.initials: H
authors.lastname: Liu
authors.forename: Xiang
authors.initials: X
authors.lastname: Gao
authors.forename: Hui-chang
authors.initials: HC
authors.lastname: Bi
authors.forename: Xue-ding
authors.initials: XD
authors.lastname: Wang
authors.forename: Bai-li
authors.initials: BL
authors.lastname: Chen
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.forename: Li-zi
authors.initials: LZ
authors.lastname: Zhao
authors.forename: Guo-ping
authors.initials: GP
authors.lastname: Zhong
authors.forename: Pin-jin
authors.initials: PJ
authors.lastname: Hu
authors.forename: Min-hu
authors.initials: MH
authors.lastname: Chen
authors.forename: Ming
authors.initials: M
authors.lastname: Huang
mesh_terms: D000328:Adult; D000368:Aged; D004912:Erythrocytes / Q000201:enzymology*; D005260:Female; D006801:Humans; D007041:Hypoxanthine Phosphoribosyltransferase / Q000378:metabolism*; D015212:Inflammatory Bowel Diseases / Q000378:metabolism* / Q000628:therapy*; D007970:Leukopenia / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism; D008297:Male; D008780:Methyltransferases / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011379:Prognosis; D013866:Thioguanine / Q000097:blood*
chemical_list: D008780:Methyltransferases; C022745:thiopurine methyltransferase; D007041:Hypoxanthine Phosphoribosyltransferase; D013866:Thioguanine